Cardiac hypertrophy is a major predictor of heart failure and of morbidity and mortality in developed countries. Many hormones and growth factors induce cardiac hypertrophy via activation of members of the phospholipase C (PLC) family. The expression pattern of the PLC beta isozyme subfamily was investigated in neonatal rat cardiomyocytes after stimulation with different hypertrophic stimuli, Under control conditions and after stimulation with norepinephrine, cardiomyocytes expressed similar amounts of PLC beta 3 mRNA. In the presence of fetal calf serum (FCS), additional expression of PLC beta 1 was induced. Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) both induced a substantial increase in PLC beta 3 mRNA expression. The response to GH could not be abolished by the ICE-I receptor blocker ICE-I analogue indicating an ICE-I-independent action of GH, The upregulation of PLC beta 3 by ICE-I was abolished by preincubation of cardiomyocytes with the ICE-I receptor antagonist IGF-I analogue, the tyrosine kinase inhibitor genistein, the extracellular signal-related kinase (ERK) inhibitor PD 98059, the phosphatidylinositol-3(PI-3) kinase inhibitor wortmannin and the p70 S6 kinase inhibitor rapamycin. Induction of the immediate early genes c-myc, c-fos, and c-jun by ICE-I was abolished by preincubation with antisense oligos against PLC beta 3, It is concluded that the expression of PLC beta isozymes in cardiomyocytes is differentially regulated by different hypertrophic stimuli. The upregulation of PLC beta 3 by ICE-I is dependent on the activity of tyrosine kinase, ERR, PI3 kinase, and p70 S6 kinase and PLC beta 3 expression seems to be required for the induction of immediate early genes by IGF-I. The involvement of the PLC beta subfamily in signal transduction of receptors other than G-protein-coupled receptors is suggested.